U.S. patent application number 12/449152 was filed with the patent office on 2010-05-13 for therapeutic agent for pain disease.
This patent application is currently assigned to NIPPON ZOKI PHARMACEUTICAL CO., LTD.. Invention is credited to Yoshitaka Nakazawa.
Application Number | 20100121040 12/449152 |
Document ID | / |
Family ID | 38769833 |
Filed Date | 2010-05-13 |
United States Patent
Application |
20100121040 |
Kind Code |
A1 |
Nakazawa; Yoshitaka |
May 13, 2010 |
THERAPEUTIC AGENT FOR PAIN DISEASE
Abstract
Disclosed is an analgesic agent for a non-inflammatory pain
disease, which comprises a sialic acid or a pharmaceutically
acceptable salt thereof as an active ingredient. The sialic acid
which is an active ingredient for the agent has an analgesic effect
on a disease model animal of neurogenic pain which is a
non-inflammatory pain. Therefore, the analgesic agent is useful as
a pharmaceutical agent for the treatment of a non-inflammatory pain
disease such as a neurogenic pain disease, e.g. trigeminal
neuralgia, postherpetic neuralgia, entrapment neuropathy, complex
regional pain syndrome, diabetic neuropathy, traumatic neuropathy,
phantom limb pain, central pain after spinal cord injury or stroke,
and neuropathy caused by pharmacotherapy or radiation therapy, or
the like.
Inventors: |
Nakazawa; Yoshitaka; (Hyogo,
JP) |
Correspondence
Address: |
OLIFF & BERRIDGE, PLC
P.O. BOX 320850
ALEXANDRIA
VA
22320-4850
US
|
Assignee: |
NIPPON ZOKI PHARMACEUTICAL CO.,
LTD.
Osaka-shi
JP
|
Family ID: |
38769833 |
Appl. No.: |
12/449152 |
Filed: |
February 6, 2008 |
PCT Filed: |
February 6, 2008 |
PCT NO: |
PCT/JP2008/051920 |
371 Date: |
October 14, 2009 |
Current U.S.
Class: |
536/17.2 ;
536/4.1 |
Current CPC
Class: |
A61K 31/7012 20130101;
C07H 7/027 20130101; A61P 25/00 20180101; A61P 29/00 20180101; A61P
25/04 20180101 |
Class at
Publication: |
536/17.2 ;
536/4.1 |
International
Class: |
C07H 7/027 20060101
C07H007/027 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 8, 2007 |
JP |
2007-028721 |
Claims
1. An analgesic agent for non-inflammatory pain diseases containing
sialic acid or a pharmaceutically acceptable salt thereof as an
effective ingredient.
2. An analgesic agent for non-inflammatory pain diseases containing
only sialic acid or a pharmaceutically acceptable salt thereof as
an effective ingredient.
3. The analgesic agent according to claim 1 or 2, wherein the
non-inflammatory pain is neuropathic pain.
4. The analgesic agent according to claim 3, wherein it is for
trigeminal neuralgia, postherpetic neuralgia, strangulated
neuropathy, complex regional pain syndrome (CRPS), diabetic
neuropathy, neuropathy caused by trauma, phantom limb pain, central
pain, or neuropathic pain caused by drug therapy or radiation
therapy.
5. The analgesic agent according to any of claims 1 to 4, wherein
sialic acid is N-acetylneuraminic acid.
6. The analgesic agent according to any of claims 1 to 5, wherein
it is an oral agent.
Description
TECHNICAL FIELD
[0001] The present invention relates to an analgesic agent for
non-inflammatory pain diseases containing sialic acid or a
pharmaceutically acceptable salt thereof as an effective
ingredient.
BACKGROUND ART
[0002] Sialic acid is a general name for acyl derivatives of
neuraminic acid. Although many kinds of sialic acids are present in
the natural world, N-acetylneuraminic acid is most abundant among
them and then the rate of N-glycolylneuraminic acid follows. Sialic
acid is widely distributed in living organisms as a constituent for
glycoprotein, glycolipid, glycopeptide, etc. It exits particularly
on the cell membrane surfaces of animals and microbes bearing
important biological functions such as participation in specific
recognition mechanism of cells. Sialic acid has been regarded as
important both medically and pharmaceutically as a substance
participating in cancer, inflammation, immune, viral infection,
cell differentiation, hormone receptor, etc. and various studies
have been carried out for sialic acid and derivatives thereof.
[0003] During the course of repeated studies for pharmacological
actions of sialic acid, the present inventors have found that
sialic acid has a specific analgesic action. "Pain" is broadly
classified into inflammatory pain which is caused by the
inflammation of tissues by damage, etc. followed by releasing the
algesic substances and physiological pain (nociceptive pain) as
well as neuropathic pain which is not accompanied by the
inflammation as such. The neuropathic pain is a general name for
the pain caused by damage and dysfunction of central nerve and
peripheral nerve and also for the non-inflammatory pain such as
neuropathy, etc. by drug therapy or radiation therapy. Neuropathic
pain causes, in addition to spontaneous pain, the symptoms such as
hyperalgesia where pain threshold to nociceptive pain lowers and
sharp pain (allodynia) induced by tactile stimulation which usually
does not induce the pain. Once the morbid state is completed, it
turns chronically whereby the outcome is very intractable unlike
the inflammatory pain. Examples of the neuropathic pain disease
include trigeminal neuralgia, postherpetic neuralgia, strangulated
neuropathy (thoracic outlet syndrome, carpal tunnel syndrome,
spinal canal stenosis, etc.), complex regional pain syndrome
(CRPS), diabetic neuropathy, neuropathy caused by trauma, phantom
limb pain and central pain after spinal damage or cerebral
apoplexy.
[0004] At present, nonsteroidal analgesics, nonopioid analgesics,
narcotic analgesics, etc. have been used for inflammatory pain and
the therapeutic methods are able to be said to be almost
established. With regard to non-inflammatory pain such as
neuropathic pain however, although clarification for pathogenic
mechanism has been already carried out, effective therapeutic drugs
are little and there have been demanded clarification of morbid
state and established therapeutic method therefor. The present
inventors have found that sialic acid shows an analgesic action to
model animals in morbid state of non-inflammatory pain and achieved
the present invention. Although it has been reported already that
sialic acid exhibits an anti-inflammatory action (refer to Patent
Documents 1 and 2), there has been neither disclosure nor
suggestion at all for its analgesic action to non-inflammatory
pain.
[0005] Patent Document 1 Japanese Patent Laid-Open Publication No.
62/145,015
[0006] Patent Document 2: Japanese Patent Laid-Open Publication No.
01/163,125
DISCLOSURE OF THE INVENTION
[0007] [Problems that the Invention is to Solve]
[0008] An object of the present invention is to provide an
analgesic agent for non-inflammatory pain diseases containing
sialic acid or a pharmaceutically acceptable salt thereof as an
effective ingredient.
[Means for Solving the Problems]
[0009] The present inventors have found that, since sialic acid
shows an analgesic action to model animals in morbid state of
non-inflammatory pain, it is useful as an analgesic agent for
non-inflammatory diseases such as neuropathic pain whereby the
present invention has been achieved.
ADVANTAGES OF THE INVENTION
[0010] Sialic acid which is an effective ingredient of the drug of
the present invention showed an analgesic action to model animals
in morbid state of neuropathic pain which is a non-inflammatory
pain. Accordingly, the analgesic agent of the present invention is
useful as a drug for the treatment of non-inflammatory pain
diseases such as neuropathic pain.
BEST MODE FOR CARRYING OUT THE INVENTION
[0011] The present invention relates to an analgesic agent to
non-inflammatory pain diseases containing sialic acid or a
pharmaceutically acceptable salt thereof as an effective
ingredient.
[0012] Sialic acid which is an effective ingredient of the
analgesic agent of the present invention include the
pharmaceutically acceptable salts of thereof with alkali metal such
as sodium or potassium, with alkaline-earth metal such as calcium,
magnesium or barium, with other metal such as aluminium or zinc,
with organic amine or with ammonium. These salts can be produced
from sialic acid in a free form, or converted reversibly, in
accordance with a known method. Existence of not less than 15 kinds
of sialic acid has been known and many of them are N-acetyl or
N-glycolyl substances and have N-acyl or O-acyl group. Any of them
is able to be used in the present invention. Preferred examples
thereof include N-acetylneuraminic acid which exists most
abundantly in the natural world and is a representative sialic acid
and a pharmaceutically acceptable salt thereof. Acute toxicity of
N-acetylneuraminic acid is disclosed in Patent Document 1 and the
toxicity is shown to be very low and safe. With regard to sodium
N-acetylneuraminate, it is also shown to be very lowly toxic as a
result of acute toxicity tests (refer to Example 8 of the Japanese
Examined Patent Publication No. 63/028,411).
[0013] When the steric isomers such as cis-trans isomer, optical
isomer and conformational isomer, or hydrate and metal complexes of
the sialic acid of the present invention exist, the present
invention includes any and all of them.
[0014] The sialic acid of the present invention can be made into
pharmaceutical preparations by a combination with a suitable
pharmaceutical carriers or diluents according to any conventional
methods, for example, preparations for oral administrations (e.g.
tablets, capsules, powders, liquids, etc.) and for parenteral
administrations (e.g. for subcutaneous, intravenous, intramuscular,
intrarectal and intranasal administrations). At preparing, the
sialic acid of the present invention may also be used in the form
of the pharmaceutically acceptable salt, and can be used either
solely or jointly together with other pharmaceutically effective
ingredients.
[0015] As to an orally administering preparation, the sialic acid
per se or together with an appropriate additive such as an
excipient, a binder, a disintegrating agent, a lubricant, a bulking
agent, a moisturizer, a buffer, a preservative or a flavor is able
to be made into tablets, diluted powder, granules or capsules.
Furthermore, depending upon the type of the disease and patient, it
is possible to prepare other preparations than those which were
mentioned already, for example, suitable preparations for the
therapy, such as injections, suppositories, inhalations, aerosols,
syrups, collyriums, medicines for external use (e.g. ointments),
etc.
[0016] The preferred dose of the analgesic agent of the present
invention may vary depending upon the object to be administered the
patient, form of the preparation, method for the administration,
term for the administration, etc. and, in order to achieve a
desired effect, 10-5000 mg per day, preferably 50-3000 mg per day
may be usually given to common adults by oral route. In the case of
a parenteral administration such as by injection, lower doses than
the above given dose by oral route have an effect.
EXAMPLES
Test for Analgesic Effect
[0017] Test for analgesic effect was conducted using Chung model
rats which are models of neuropathic pain. Male rats of Wistar
strain of 9 weeks age were used as experimental animals and model
rats were prepared according to a method of Kim and Chung (Pain,
vol. 50, pages 355 to 363, 1992). Thus, when they were in 10 weeks
age, rat L5 spinal nerve was exposed and the periphery side of L5
dorsal root ganglion was strongly ligated with 5-0 silk yarn under
anesthetizing with pentobarbital (40 mg/kg, intraperitoneal
administration) to conduct a nerve damage. The animals were placed
in a transparent acrylic cage where the bottom was wire net, 50%
reaction threshold values were calculated by an up-down method
using a von Frey filament (manufactured by North Coast Medical
Inc.) according to a method of Chaplan, et al. (J. Neurosci.
Method, vol. 53, pages 55 to 63, 1994) and the effect of the test
substance to allodynia was measured. Those which showed a stable
decrease in threshold value of from 1 g to less than 4 g by the
measurement of 50% reaction threshold values after the spinal nerve
damage were used for the test. In those experimental animals, each
group comprised seven animals using the 50% reaction threshold
values after the nerve damage as an index and the group
constitution was done in such a manner that mean values of a nerve
damage control group and of a test substance-administered group
were made nearly uniform.
[0018] N-acetylneuraminic acid as a test substance was
intraperitoneally administered in a single dose (120 mg/kg). A 0.5%
CMC-Na (w/v) solution/physiological saline was similarly
administered to the nerve damage control group (control group).
After 30 minutes from the administration of a test substance, pain
tests were conducted and the calculated 50% reaction threshold
values were expressed in terms of mean value.+-.standard deviation
for each group. An example of the results of the above test is
shown in Table 1. Test for significant difference was conducted
using Dunnett's multiple comparison method for a comparison in
multiple groups between the nerve damage control group and the test
substance-administered group and it was judged that P<0.05 is
significantly different.
TABLE-US-00001 TABLE 1 50% Reaction Threshold Values (g) After 30
minutes from Groups Before Administration Administration Nerve
Damage 2.66 .+-. 0.25 2.84 .+-. 0.37 Control N-Acetylneuraminic
2.63 .+-. 0.21 6.74 .+-. 1.64* Acid *P < 0.05 (Dunnett's
Multiple Comparison Test)
[0019] Further, in the same manner as the above test,
N-acetylneuraminic acid as a test substance was orally administered
in a single dose (300 mg/kg). Injection solvent was administered to
a nerve damage control group (control group) in the same manner.
After 60 minutes from the administration of a test substance, pain
tests were conducted and the 50% reaction threshold values were
calculated. Numbers of the animals were eight for each of the nerve
damage control group and the test substance-administered group. An
example of the above test result is shown in Table 2.
TABLE-US-00002 TABLE 2 50% Reaction Threshold Values (g) After 60
minutes from Groups Before Administration Administration Nerve
Damage 2.76 .+-. 0.20 2.96 .+-. 0.36 Control N-Acetylneuraminic
2.75 .+-. 0.15 4.81 .+-. 0.35* Acid *P < 0.05 (Dunnett's
Multiple Comparison Test)
[0020] As a result of conducting the above analgesic effect tests,
there was no big change in the 50% reaction threshold values before
and after administration of the CMC-Na solution/physiological
saline or the injection solvent in the nerve damage control group
(control group) in both of single intraperitoneal injection and
single oral administration. On the contrary, the 50% reaction
threshold value in the test substance (N-acetylneuraminic acid)
administered group showed a significant rise as compared with the
nerve damage control group whereby the anti-allodynia action of the
present invention compound or, in other words, a significant
anti-analgesic effect to neuropathic pain was noted.
INDUSTRIAL APPLICABILITY
[0021] As shown in the above analgesic effect test, sialic acid
exhibited a significant analgesic effect to model animals in morbid
state of neuropathic pain. Unlike the inflammatory pain caused by
inflammation, the neuropathic pain is morbid pain without
inflammation caused by dysfunction of peripheral or central nerve
itself. Accordingly, the analgesic agent of the present invention
is useful as a drug for the treatment of non-inflammatory pain
diseases such as neuropathic pain disease, for example, trigeminal
neuralgia, postherpetic neuralgia, strangulated neuropathy
(thoracic outlet syndrome, carpal tunnel syndrome, spinal canal
stenosis, etc.), complex regional pain syndrome (CRPS), diabetic
neuropathy, neuropathy caused by trauma, phantom limb pain, central
pain after spinal damage or cerebral apoplexy and neuropathic pain
caused by drug therapy or radiation therapy.
* * * * *